The long-term objectives of the proposed research program are to elucidate the biological role of tyrosine-specific protein kinases (PTKs) and to explore the biochemical consequences of their deregulation. These enzymes play a crucial, albeit still enigmatic role in the signal transduction pathways responsible for cell growth and differentiation. Upon the loss of key regulatory controls, either through the over-expression or mutation of specific PTKs, the oncogenic potential of these enzymes is unleashed. Regulatory agents, which disturb or otherwise alter the myriad protein-protein recognition events that drive signal transduction pathways, will be extraordinary useful in helping to decipher the role of specific enzymes in these pathways. In addition, these regulatory agents may ultimately provide the foundation upon which therapeutically useful components can be devised. The proposed research aims to develop (1) peptide/non-peptide conjugates directed against the SH2 and SH3 domains of PTKs, based upon our recent acquisition o f high affinity SH2-targeted conjugates; (2) non- phosphorylatable PTK active site-directed ligands based upon our previous observation that the active site specificity of PTKs toward unnatural ligands is surprising variable; (3) bivalent ligands that block both the kinase activity and the intracellular localization of PTKs; (4) photo-compliant modulators of PTK action; and (5) an assessment of the in vivo efficacy of these PTK regulatory agents.